Pharmaceutical Formulation Comprising Cibenzoline or Salt Thereof

Abstract

A pharmaceutical formulation including an immediate release layer and an extended release layer according to the present disclosure has a biphasic dissolution profile, such that it is possible to quickly reach an effective plasma concentration of cibenzoline at the early stage, and the effective plasma concentration may be continuously maintained at the late stage. Therefore, the medicinal effect of cibenzoline may be maintained only by an administration of a single formulation once a day.

1 . A pharmaceutical formulation comprising about 150 to about 450 mg of S(−)-cibenzoline or a pharmaceutically acceptable salt thereof,
 wherein the pharmaceutical formulation includes an immediate release layer and an extended release layer. 
 
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein in the pharmaceutical formulation, a weight ratio of the S(−)-cibenzoline or the pharmaceutically acceptable salt thereof contained in the immediate release layer to the S(−)-cibenzoline or the pharmaceutically acceptable salt thereof contained in the extended release layer is about 1:4 to about 1:1. 
     
     
         3 . The pharmaceutical formulation of  claim 1 , wherein an extended release agent is contained in the pharmaceutical formulation in an amount of about 5 to about 30% with respect to the total weight of the extended release layer. 
     
     
         4 . The pharmaceutical formulation of  claim 3 , wherein a viscosity of the extended release agent is about 1,500 to about 200,000 centipoise (cps). 
     
     
         5 . The pharmaceutical formulation of  claim 3 , wherein the extended release agent is selected from hydroxyethyl cellulose, hydroxypropyl methylcellulose, and a salt or derivative thereof, polyethylene oxide and a salt or derivative thereof, sodium carboxymethyl cellulose, carbomer, polyvinyl acetate, and a mixture thereof. 
     
     
         6 . The pharmaceutical formulation of  claim 1 , wherein a disintegrant is contained in the pharmaceutical formulation in an amount of about 1 to about 10% with respect to the total weight of the immediate release layer. 
     
     
         7 . The pharmaceutical formulation of  claim 6 , wherein the disintegrant is selected from carboxymethylcellulose calcium, pregelatinized starch, sodium starch glycolate, crospovidone (polyplasdone), croscarmellose sodium, low-substituted hydroxypropylcellulose, alginic acid, powdered cellulose, starch, sodium alginate, and a mixture thereof. 
     
     
         8 . The pharmaceutical formulation of  claim 1 , wherein the immediate release layer contains:
 (a-1) S(−)-cibenzoline or a pharmaceutically acceptable salt thereof, and   (a-2) a disintegrant in an amount of about 1 to about 10% with respect to the total weight of the immediate release layer, and   the extended release layer contains:   (b-1) S(−)-cibenzoline or a pharmaceutically acceptable salt thereof, and   (b-2) an extended release agent in an amount of about 5 to about 30% with respect to the total weight of the extended release layer.   
     
     
         9 . The pharmaceutical formulation of  claim 8 , wherein the immediate release layer contains:
 (a-1) S(−)-cibenzoline or a pharmaceutically acceptable salt thereof in an amount of about 25% to about 40% with respect to the total weight of the immediate release layer; and   (a-2) a disintegrant selected from carboxymethylcellulose calcium, pregelatinized starch, sodium starch glycolate, crospovidone (polyplasdone), croscarmellose sodium, low-substituted hydroxypropylcellulose, alginic acid, powdered cellulose, starch, sodium alginate, and a mixture thereof in an amount of about 1 to about 10% with respect to the total weight of the immediate release layer, and   the extended release layer contains:   (b-1) S(−)-cibenzoline or a pharmaceutically acceptable salt thereof in an amount of about 30% to about 40% with respect to the total weight of the extended release layer; and   (b-2) an extended release agent selected from hydroxyethyl cellulose, hydroxypropyl methylcellulose, and a salt or derivative thereof, polyethylene oxide and a salt or derivative thereof, sodium carboxymethyl cellulose, carbomer, polyvinyl acetate, and a mixture thereof in an amount of about 5 to about 30% with respect to the total weight of the extended release layer.   
     
     
         10 . The pharmaceutical formulation of  claim 8 , wherein the immediate release layer or the extended release layer contains an excipient selected from microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, magnesium stearate, colloidal silicon dioxide, lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, saccharides, polyvinylpyrrolidone, copovidone, gelatin, sucrose, methyl cellulose, ethyl cellulose, light anhydrous silicic acid, talc, stearic acid, and a mixture thereof. 
     
     
         11 . The pharmaceutical formulation of  claim 8 , wherein in the pharmaceutical formulation, a weight ratio of the S(−)-cibenzoline or the pharmaceutically acceptable salt thereof contained in the immediate release layer to the S(−)-cibenzoline or the pharmaceutically acceptable salt thereof contained in the extended release layer is about 1:4 to about 1:1. 
     
     
         12 . The pharmaceutical formulation of  claim 1 , wherein in the pharmaceutical formulation, a plasma concentration [C] of the S(−)-cibenzoline or the pharmaceutically acceptable salt thereof is about 150 ng/mL or more for about 6 hours to about 18 hours out of 24 hours. 
     
     
         13 . The pharmaceutical formulation of  claim 1 , wherein the pharmaceutical formulation satisfies a biphasic dissolution profile in a dissolution test. 
     
     
         14 . The pharmaceutical formulation of  claim 13 , wherein the biphasic dissolution profile satisfies the following dissolution profile:
 1) about 30 to about 50% of the total weight of the S(−)-cibenzoline or the pharmaceutically acceptable salt thereof is released within about 30 minutes, and   2) thereafter, a release of about 90% or more of the total weight of the S(−)-cibenzoline or the pharmaceutically acceptable salt thereof is achieved within about 12 hours.   
     
     
         15 . A pharmaceutical formulation for treating hypertrophic cardiomyopathy comprising the pharmaceutical formulation of  claim 1 . 
     
     
         16 . A kit comprising the pharmaceutical formulation of  claim 1  and instructions that instruct a patient to administer the pharmaceutical formulation once a day.